CLL/SLL,   FL,  MZL

Obinutuzumab plus lenalidomide is effective and well tolerated in patients with indolent lymphomas

The combination of obinutuzumab and lenalidomide is associated with high rates of response and a manageable adverse event (AE) profile in patients with indolent lymphoma, according to the results of two studies presented at the 61st American Society of Hematology (ASH) Meeting & Exposition, Orlando, US, in December 2019. The studies, which involved patients with previously-untreated, high-tumor-burden follicular lymphoma (FL)1 and relapsed small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), or FL2, adds to the growing weight of evidence supporting this chemotherapy-free regimen in the treatment of lymphoma, encouraging further evaluation in both the frontline and salvage settings.

Obinutuzumab is a humanized, type II anti-CD20 monoclonal antibody that enhances antibody-dependent cellular cytotoxicity and increases cell death induction compared with rituximab.3 Lenalidomide is a potent immunomodulatory agent that enhances T cell- and natural killer cell-mediated immunity, and inhibits both angiogenesis and the production of proinflammatory cytokines.4 Lenalidomide has previously shown to work synergistically with another anti-CD20 antibody, rituximab, in patients with FL. In a phase III trial, RELEVANCE, the combination (R2 regimen) was equally effective as chemotherapy in treating patients with newly diagnosed FL.5 In another phase III trial, AUGMENT, the R2 regimen had superior efficacy compared with rituximab alone in patients with relapsed or refractory FL.6,7 Recent studies investigate the hypothesis that lenalidomide plus obinutuzumab might be more effective and equally well-tolerated.3

Phase II study in untreated FL1

In the first study, presented in Orlando by Loretta J. Nastoupil, The University of Texas, MD Anderson Cancer Center, Houston, US, 90 patients with previously untreated, Stage II, III, or IV high-tumor-burden FL (Grade 1–3a) received:

  • Obinutuzumab: 1000mg on Days 1, 8, and 15 of Cycle 1, Day 1 of Cycles 2–6, and Day 1 of even-numbered cycles for Cycles 8–30, with a 28-day cycle length
  • Lenalidomide: 20mg on Days 1–21 of Cycles 1–6
    • Patients in a complete response (CR) after six cycles received lenalidomide (10mg) on Days 1–21 for Cycles 7–18
    • Patients in a partial response (PR) after six cycles continued with lenalidomide (20mg) for the next 3–6 cycles or until a CR, whichever occurred first, after which the lenalidomide dose was reduced to 10mg on Days 1–21 for the remainder of 18 cycles

Baseline patient characteristics are shown in Table 1.

Table 1. Baseline patient characteristics

 

N= 90 (%)

Median age, years (range)

58 (33–84)

Male

47 (52)

ECOG PS

 

              0

67 (74)

              1

23 (26)

Ann Arbor stage

 

              II           

9 (10)

              III          

22 (24)

              IV

58 (64)

FL grade

 

              1–2

72 (80)

              3a         

18 (20)

FLIPI score

 

              Low risk (0–1)

19 (21)

              Intermediate risk (2)             

33 (37)

              High risk (3–5)

38 (42)

LDH > ULN

14 (16)

Bulky disease (> 7cm)

31 (34)

ECOG, Eastern Cooperative Group; FL, follicular lymphoma; FLIPI, Follicular Lymphoma International Prognostic Index; LDH, lactate dehydrogenase; PS, performance status; ULN, upper limit of normal

Results
  • With a median follow-up of 25 months (range, 6–35 months):
  • Estimated 2-year progression-free survival (PFS): 96% (95% confidence interval [CI], 92–100%)
  • In a first response assessment, 87% of patients had achieved a CR, and the overall response rate (ORR) was 94%
  • In a best response assessment, 94% of patients had achieved a CR, and the ORR was 96%
  • No deaths were observed during this study. The most common Grade 3/4 treatment-emergent adverse events were neutropenia, rash, fatigue, and diarrhea
  • There were two thromboembolic events and two second malignancies
  • 18 patients (20%) discontinued treatment; 13 (14%) as a result of toxicity

Despite the relatively short follow-up in this study, Dr Nastoupil described the results as “promising.”

“In my opinion, this phase II study suggests that this is a highly active and well tolerated therapy and future study is warranted,” she concluded.

Watch an interview with Loretta Nastoupil, who discusses this study during the 61st ASH meeting in Orlando, here.

Phase I/II study in relapsed indolent lymphoma2

The second study, presented by Nathan H. Fowler, The University of Texas, MD Anderson Cancer Center, Houston, US, was designed primarily to determine the maximum tolerated dose and efficacy of the combination therapy in patients with relapsed indolent lymphoma. Sixty-six patients with relapsed SLL, MZL, or FL Grade 1–3a were treated with a target dose of lenalidomide (20mg) plus obinutuzumab (1000mg):

  • Lenalidomide was administered on Days 2–22 of a 28-day cycle
  • Obinutuzumab was administered on Days 1, 8, 15, and 22 in Cycle 1 and Day 1 in subsequent cycles
  • Combination treatment was given for up to 12 cycles in responding patients
  • In the absence of progression or toxicity, single agent obinutuzumab was continued every two months for a maximum of 30 months on study

No dose-limiting toxicities were observed in the dose escalation phase of the study and the majority of patients received the target dose. Baseline characteristics are shown in Table 2.

Table 2. Baseline characteristics

 

N= 66 (%)

Median age, years (range)

64 (36–81)

Male

35 (53)

Histology at diagnosis

 

              MZL

4 (6)

              SLL

5 (8)

              FL

57 (86)

Prior lines of therapy

 

              1           

14 (23)

              2           

31 (47)

              ≥ 3

17 (26)

              Rituximab refractory

16 (24)

              Prior chemotherapy backbone

50 (76)

              Prior lenalidomide + rituximab

3 (5)

Results
  • Response rates were high and similar, regardless of histology at diagnosis, line of therapy, and whether or not the patient had progressed within two years (Table 3)
  • With a median follow-up of 17.7 months:
    • The projected 2-year PFS was 73% (95% CI, 58–83%)
    • The projected 2-year OS was 94% (95% CI, 77–98%)

Table 3. Response rates

 

MZL/SLL

(n= 9)

FL

(n= 57)

Rituximab-refractory

(n= 16)

≥ 3rd-line

(n= 31)

POD24

(n=27)

ORR, n (%)

8 (88)

57 (100)

16 (100)

30 (97)

26 (96)

CR/CRu

4 (44)

43 (75)

10 (63)

21 (68)

18 (66)

PR

4 (44)

14 (25)

6 (37)

9 (29)

8 (30)

SD, n (%)

12 (25)

0 (0)

0 (0)

1 (3)

1 (4)

PD, n (%)

0 (0)

0 (0)

0 (0)

0 (0)

0 (0)

CR, complete response; CRu, unconfirmed complete response; FL, follicular lymphoma; MZL, marginal zone lymphoma; ORR, overall response rate; PD, progressive disease; POD24, progression of disease within 2 years; PR, partial response; SD, stable disease; SLL, small lymphocytic lymphoma

  • Grade 3/4 anemia, neutropenia, and thrombocytopenia occurred in 2%, 21%, and 11% of patients, respectively
  • The most common Grade 3/4 nonhematologic AEs were infection, fatigue, rash, cardiac disorders, cough, and sepsis
  • Five secondary malignancies were reported; four of these were in one patient
Conclusions

The combination of lenalidomide and obinutuzumab seems to be effective, with high response rates achieved in patients with relapsed indolent lymphoma, including those who are refractory to rituximab. The toxicity profile of the combination was reported to be manageable and similar to that observed with lenalidomide and rituximab.

“Larger phase III trials are needed to truly understand if this regimen is better than R2 in the relapse setting,” concluded Dr Fowler.

References
  1. Nastoupil L.J. et al. Results of a phase II study of obinutuzumab in combination with lenalidomide in previously untreated, high tumor burden follicular lymphoma (FL); 2019 Dec 7. Oral Abstract #125: 61st American Society of Hematology (ASH) Meeting & Exposition, Orlando, US
  2. Fowler N.H. et al. A phase I/II study of lenalidomide plus obinutuzumab in relapsed indolent lymphoma; 2019 Dec 8. Oral Abstract #348: 61st American Society of Hematology (ASH) Meeting & Exposition, Orlando, US
  3. Houot R. et al. Obinutuzumab plus Lenalidomide (GALEN) for the treatment of relapse/refractory aggressive lymphoma: a phase II LYSA study. Leukemia. 2019 Mar; 33(3):776–780. DOI: 10.1038/s41375-018-0282-y
  4. Revlimid (lenalidomide) 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg hard capsules. Summary of Product Characteristics. Celgene Europe B.V. https://www.ema.europa.eu/en/documents/product-information/revlimid-epar-product-information_en.pdf [Accessed 2019 December 15]
  5. Morschhauser F. et al. Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma. N Engl J Med. 2018 Sep 6; 379(10):934–947. DOI: 10.1056/NEJMoa1805104
  6. Leonard J.P. et al. AUGMENT: A Phase III Study of Lenalidomide Plus Rituximab Versus Placebo Plus Rituximab in Relapsed or Refractory Indolent Lymphoma. J Clin Oncol. 2019 May 10; 37(14):1188–1199. DOI: 10.1200/JCO.19.00010
  7. Leonard J.P. et al. Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance). J Clin Oncol. 2015 Nov 1; 33(31):3635–3640. DOI: 10.1200/JCO.2014.59.9258
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